After a myocardial infarction the non-infarcted myocardium undergoes a remodeling process involving structural and biochemical changes resulting in compensatory myocardial hypertrophy, but which eventually leads to heart failure. This sequence of events is worsened by female gender and by genetic (essential) hypertension. The reason for this worse outcome in women and in patients with hypertension is not clear. The central hypothesis of this grant proposal is that the remodeling process and the occurrence of heart failure in individual hearts is dependent not only on infarct size, but is similarly dependent on genetic factors and cardiovascular risk factors, specifically hypertension. It is further hypothesized that the transition to heart failure will be preceded by key molecular changes in gene expression. To test these hypotheses we will induce myocardial infarction in an animal model of genetic hypertension and test for key molecular changes associated with post-Ml remodeling and the transition to heart failure. The overall goal is to identify pivotal molecular steps in the transition to failure that will provide insight into novel and/or integrated intervention approaches. The specific aims are: 1. To characterize the temporal and spatial cell-specific molecular changes in post-MI remodeled myocardium with a strategic panel of molecular probes found to be informative in other models of cardiac pathology (c-fos, ANF, B-MHC, SR-Ca++-ATPase, Na, K-ATPase). 2. To define the gender-specific effects of hypertension-induced hypertrophy in post-MI remodeling and the transition to heart failure. 3. To determine the role of Na,K-ATPase on changes in gene expression during post-Ml remodeling by comparing Dahl R rats (wild type), Dahl S rats (mutant) and transgenic Dahl S rats with the wild type al Na,K-ATPase transgene [TgRal-Ral]. 4. To determine the role of post-MI hypertrophy response genes in the transition to failure via strategic transgenic rat models using an inducible and cardiac-directed biogenic system. Accordingly, at different time points post-MI hemodynamic studies will be performed and correlated with morphologic and molecular analysis of the hearts. Temporal and spatial cell-specific changes in gene expression will be assessed by in situ hybridization and immunocytochemistry. Integrating these molecular, physiologic and genetic observations will increase understanding of the molecular mechanisms of post-MI heart failure, and potentially improve its therapy.